Treating smoking dependence in depressed alcoholics.

Alcoholism and nicotine dependence share many neurobiological underpinnings; the presence of one drug can cause a person to crave the other. Depressive illness can complicate comorbid alcohol and nicotine dependence by exacerbating the negative affect encountered during attempts to abstain from one or both drugs. Given the morbidity and mortality associated with cigarette smoking, it is imperative to identify treatments to promote smoking cessation and address comorbid psychiatric conditions contemporaneously. Pharmacotherapeutic options demonstrating varying degrees of efficacy and promise in preclinical and clinical studies include nicotine replacement therapy (NRT), selective serotonin reuptake inhibitors (SSRIs), bupropion, varenicline, tricyclic antidepressants, and bupropion plus NRT. Topiramate has shown potential for promoting smoking cessation in alcoholics, although its safety in depressed patients has not been fully explored. The efficacy of medications for treating nicotine dependence is generally enhanced by the inclusion of behavioral interventions such as cognitive behavioral therapy. When group cohesion and social support are stressed, success rates increase among depressed smokers undergoing smoking cessation treatment. Additional treatment strategies targeting dually dependent individuals with comorbid psychiatric disorders, including special populations such as women and adolescents, await further investigation.

cortico-mesolimbic dopamine system, which is critical for expressing the posi tive reinforcing effects of these drugs (Hemby et al. 1997;Wise 1996). Preclinical studies also show that neu rochemical interactions between alco hol and nicotine can augment the rein forcing effects of the combination (Soderpalm et al. 2000) and that the presence of one drug can trigger drugseeking behavior for the other (Lê et al. 2003).
Tobacco and alcohol seem to trigger similar central opioid peptide responses; therefore, both substances often are used as self-medication for comorbid affective disorder (Abrams et al. 1992;Hertling et al. 2005;Pomerleau and Pomerleau 1987). Thus, Currie and colleagues (2001) have suggested that people with a combined history of alcohol dependence and major depres sion are at high risk of using smoking as a means of mood enhancement. Craving for alcohol or nicotine is posi tively correlated with depression and anxiety, and alcohol-dependent patients often experience the urge to smoke in response to the discomfort associated with the urge to drink or to enhance their mood (Rohsenow et al. 1997).
Some practitioners might be reluc tant to treat nicotine dependence in mental health settings if they think that it would depress mood and increase anxiety among patients trying to over come other addictions or mental illness. Nevertheless, despite the belief that smoking cessation can trigger alcohol relapse among people dependent on both drugs, contemporary studies show that smoking cessation treatment does not cause abstinent alcoholics to relapse (Hughes and Callas 2003). Indeed, treat ment that promotes smoking cessation among smokers within an alcoholdependent population might decrease the likelihood of relapse to drinking.
The clinical approach toward treat ing people with comorbid nicotine and alcohol dependence becomes more complicated among patients who also have a depressive illness. Such individu als might smoke or drink to relieve negative affective mood states such as depression and anxiety and therefore Parts of the brain involved in alcohol/nicotine dependence and psychiatric disorders. would be expected to be more difficult to treat. This article will review some of the treatments available to help patients with comorbid alcohol and nicotine dependence and depression, discuss the limitations of these treatments, and introduce some of the new treatment approaches that might lessen the chal lenge of treating this population.

Basic Research
An understanding of the neurochemi cal mechanisms underlying the addic tive properties of alcohol and nicotine is critical for the development of potential pharmacotherapies. As with other drugs of abuse, the reinforcing effects of both alcohol and nicotine appear to be mediated, at least in part, by dopaminergic projections in the cortico-mesolimbic system (Johnson 2004;Koob 2003;Samson and Harris 1992). Alcohol, both directly and indi rectly, can increase excitatory cellular activation of dopaminergic cell bodies in the ventral tegmental area (VTA). This, in turn, leads to the facilitation of dopamine release in the nucleus accum bens (Brodie et al. 1999;Johnson 2005;Ortiz et al. 1995). The primary action by which alcohol increases dopamine in the nucleus accumbens appears to be via its effects on gamma aminobutyric acid (GABA) neurons in the VTA (for a review, see Johnson 2004). Recent evidence, however, demonstrates that alcohol also can exert its reinforc ing and dopamine-enhancing effects through activation of nicotinic acetyl choline receptors. In laboratory rats, chronic treatment with nicotine increases the reinforcing and dopamineenhancing effects of alcohol, and these effects are blocked by the nicotinic receptor antagonist mecamylamine (for a review, see Larsson and Engel 2004). These results suggest that nicotinic acetylcholine receptors in the VTA might serve as a common substrate for alcohol-nicotine interactions.
Serotonin appears to play a critical role in mediating the reinforcing effects of alcohol and nicotine, and it has been implicated in the pathophysiology of various neuropsychiatric disorders, including depression. Both alcohol and nicotine stimulate the serotonergic system. Long-term use of alcohol and nicotine can, however, produce a hypo-seroton ergic state that might trigger or worsen a depression. For instance, both chronic alcohol and nicotine administrations dose-dependently reduce the synthesis of tryptophan hydroxylase (the ratelimiting enzyme for serotonin synthesis) in the raphe nuclei, as evidenced by a diminution in the amount of serotoninand tryptophan hydroxylase-positive cells identified by immunochemistry (Jang et al. 2002). It is reasonable, therefore, to propose that the pathogenesis of alcoholand nicotine-induced mood disorders might involve alcohol-and nicotineinduced suppression of serotonin synthe sis. Taken together, these data suggest that neuromodulation of serotonin and cortico-mesolimbic dopamine, particu larly via manipulation of the nicotinic acetylcholine receptor, might reduce the reinforcing effects of both alcohol and nicotine. Thus, pharmacological agents that reduce the reinforcing effects of alco hol and nicotine by modulating these neurotransmitter systems might have potential therapeutic value for treating nicotine and alcohol dependence and comorbid depression in humans.

Pharmacotherapeutic Approaches
Nicotine replacement therapy (NRT) in combination with psychotherapy or behavioral therapy is an effective treat ment for nicotine dependence. Some research data also suggest that NRT might be beneficial in improving mood among abstinent depressed smokers (Cummings and Hyland 2005). Because the emergence of depressive symptoms during smoking cessation treatment is associated with failed quit attempts and increased probability of returning to smoking (Anda et al. 1990), alleviating such negative affective mood states is an important pharmacotherapeutic goal.
Although treating smokers with concurrent major depressive disorder requires the administration of antide pressants such as selective serotonin reuptake inhibitors (SSRIs), the utility of SSRIs in treating alcohol dependence has depended on clinical subtype. Among patients who develop problem drinking early in life, have a strong family history of alcoholism, and fre quently exhibit impulsive behaviors (i.e., early-onset or type B alcoholics), SSRIs worsen drinking outcomes (Kranzler et al. 1996). In contrast, SSRIs improve drinking outcomes among patients who develop problem drinking later in life and do not have a family history of alcoholism or a personal history of impulsivity (i.e., late-onset or type A alcoholics) (Pettinati et al. 2000). Indeed, Johnson (2000) has proposed that the variation in expression of the molecular mechanism within the sero tonin system might explain this differ ential response. Notwithstanding these findings, SSRI treatment appears to benefit alcohol-dependent patients with severe depression and suicidal ideation (Cornelius et al. 1997) but not to aid those with more moderate depressive symptoms and comorbid alcohol dependence (Pettinati et al. 2001). Further, even among depressed patients who are co-dependent on nicotine and alcohol, SSRI treatment alleviates the depressive mood but has little impact on the substance abuserelated outcomes (Torrens et al. 2005). Patients with a dual diagnosis (i.e., of depression and substance dependence) therefore need concomitant treatment of both disorders.
Bupropion is the only antidepres sant that has been approved by the Food and Drug Administration (FDA) for treating nicotine dependence. Bupropion is a tricyclic antidepressant (TCA) that inhibits noradrenergic and dopamine uptake and, at high concen trations, inhibits the firing of noradren ergic neurons in the locus coeruleus (Ascher et al. 1995). Preclinical studies also show that bupropion might act as a noncompetitive nicotinic receptor antagonist (Slemmer et al. 2000), thereby reducing the reinforcing effects of nicotine. Slow-release bupropion aids smoking cessation among smokers with a history of major depression or alcoholism. Slow-release bupropion's dose-dependent effect on smoking ces sation observed among smokers with a history of depression was comparable to the effect observed among smokers with no history of depression or alco holism (Hayford et al. 1999). However, because smokers with current depression and alcoholism (i.e., within the past year) were excluded from the study, these findings might be of limited sig nificance. Unfortunately, bupropion has not been found to be effective for treating alcohol dependence.
Bupropion is the only TCA that has been approved by the FDA as a treat ment for smoking dependence. Never theless, other nonapproved TCAs have been investigated for smoking cessation and are considered to be second-line treatments. Nortriptyline, a TCA that has both dopaminergic and adrenergic enhancing effects, has shown efficacy in treating nicotine dependence indepen dently of depression history and can reduce smoking cessation-related nega tive affect, which can be a trigger for relapse (Hall et al. 1998). Results from two separate research studies showed that TCAs such as desipramine (Mason et al. 1996) and imipramine (McGrath et al. 1996) also reduced depressive symptoms among alcoholics with comor bid depression. Although desipramine also demonstrated an effect to reduce drinking, this occurred at doses higher than that approved by the FDA, and there was increased risk of toxicity (Mason et al. 1996). TCAs can, how ever, produce several unpleasant adverse effects that limit their utility as antismoking agents. These include reducing the pleasurable effects of smoking related to its consumption by inducing drowsiness, making smoking more hazardous by increasing the potential for cardiotoxicity, and increas ing the difficulty of smoking cessation by inducing weight gain. A recent sys tematic meta-analytic review concluded that antidepressant medication only exerts a modest beneficial treatment effect among patients with combined substance use and depressive disorders. It is not a stand-alone treatment; con current therapy aimed at directly treat ing the addiction also is indicated (Nunes and Levin 2004).
The FDA recently approved a sec ond medication, varenicline, as an aid to smoking cessation. Varenicline is a selective α4 β2 partial nicotinic receptor agonist that, in the presence of nicotine, acts as a relative antagonist and diminishes nicotine's reinforcing effects. In two recent trials, varenicline admin istration resulted in quit rates signifi cantly higher than those achieved among placebo recipients Oncken et al. 2006). Indeed, the results of one of these studies suggest that varenicline might be more clinically effective than bupropion . For a review, see Johnson (2006).
Combining NRT with non-NRT pharmacotherapeutic treatments appears promising for patients with comorbid depression and nicotine dependence. For instance, combining the nicotine patch with bupropion increases absti nence rates up to 58 percent, compared with bupropion alone (49 percent), patch alone (36 percent), or placebo (23 percent) (Johnston et al. 1999). Other studies have reported similar trends. For example, bupropion plus the transdermal nicotine patch increased 6-month, self-reported abstinence rates up to 34 percent, compared with bupro pion alone (28 percent) and patch alone (15 percent) (Gold et al. 2002). In another study, bupropion combined with the nicotine patch resulted in higher 12-month abstinence rates (36 percent) compared with nicotine patch alone (16 percent), bupropion alone (30 percent), or placebo (16 percent) (Jorenby et al. 1999).
Topiramate is an anticonvulsant drug, with several mechanisms of action, that diminishes cortico-mesolimbic dopamine by facilitating GABAergic activity while inhibiting glutamatergic activity (for a review, see Johnson 2004). Johnson and colleagues (2003) have shown that up to 300 mg/day of topiramate, com pared with placebo, significantly increases abstinence from alcohol among alco hol-dependent patients receiving only brief behavioral compliance enhance ment treatment. In a subset of partici pants from the same trial, topiramate recipients compared with placebo recipients were significantly more likely to become abstinent from smoking (odds ratio = 4.46; 95 percent CI 1.08-18.39; p = 0.04). Interestingly, reductions in smoking were positively associated with drinking decreases for the topiramate group but not for the placebo group. These results suggest that topiramate might have specific antismoking effects. Topiramate did not alter mood. Study participants who received topiramate, compared with those who received the placebo, experi enced a significant weight reduction (i.e., 20 [44 percent] topiramate recipi ents experienced weight loss compared with 9 [18 percent] placebo recipients; p = 0.008) (Johnson et al. 2005). Taken together, these results demonstrate to piramate's potential as a safe and promis ing medication for treating alcoholdependent smokers. Topiramate's abil ity to induce weight loss might counter a treatment barrier reported by some in smoking cessation treatment-weight gain (Jeffery et al. 2000). A doubleblind, placebo-controlled clinical trial testing topiramate for the treatment of anger and depressive symptoms among mildly to moderately depressed women in Germany showed efficacy in primary outcome measures, which included sig nificant reductions on the Hamilton Depression Rating Scale, the State-Trait Anger Expression Inventory, the Test of Attention, and the SF-36 Health Survey (Nickel et al. 2005). Nevertheless, the type of alcohol-dependent smoker who responds best to topiramate needs to be elucidated more clearly, and research is needed to determine the safety of topiramate in treating comor bid alcohol-and nicotine-dependent patients with current or a past history of depressive illness.

Psychotherapeutic Intervention
Two psychological theories have been proposed as being related to the rela tionships among depression, alco holism, and smoking behavior. First, drug use (including that of nicotine and alcohol) might be motivated by a person's expectation of the outcome, such as a decrease in negative affect and tension. If such a person is also depressed, there might be an even greater motivation to alleviate dyspho ria or anxious mood. Second, depressed smokers with or without alcohol dependence might have less self-efficacy and, therefore, more difficulty becom ing abstinent than their nondepressed counterparts.
These models of self-medication and learned helplessness have received empirical support in research with nicotine-and alcohol-dependent popu lations. For example, smokers who identify the prevention of negative affect as their primary reason for smok ing are more likely to fail in quit attempts. When smokers become depressed, the course and prognosis of smoking cessa tion become intertwined with the pathophysiology of depression. For instance, smokers with a history of major depressive disorder are more likely to experience depressed mood during nicotine withdrawal (Breslau et al. 1991) and are at greater risk for developing recurrent episodes of major depression than are nonsmokers (Glassman et al. 2001). Depressed smokers also are more likely than nondepressed smokers to report deficits in coping resources, to adhere to the com ponents of smoking cessation treat ment, and to use cigarettes for amelio rating negative affect (Kinnunen et al. 1996). Thus, psychosocial interven tions for depressed smokers with or without alcohol use disorders might be more effective if they were focused on treating depressive symptoms simulta neously with the smoking cessation treatment. This would enable such individuals to learn healthy coping strategies, including affect regulation and stress management.
Indeed, in one of the few studies of its kind, Patten and colleagues (2002) examined the effect of depressive symp toms on smoking abstinence and treat ment adherence among smokers with a past history of alcohol dependence. They found that smokers with a his tory of alcohol dependence who also reported high levels of depressive symp toms were more likely to be abstinent from smoking at the end of treatment and at follow-up than those with low depression scores. The authors con cluded that similar to research in the nonalcoholic literature (Zelman et al. 1992), smokers who demonstrate a vulnerability to negative affect-and who might use drugs to regulate moodbenefit more from a mood manage ment-specific therapy to address their depression in addition to smoking cessation treatment.
Nevertheless, the necessity of incor porating mood management skills training for smokers with a history of depression has not been established. For instance, Hall and colleagues (1994,1998) found that mood management skills training for smokers with a his tory of major depressive disorder was most effective when there was more frequent therapist contact time than in the control group. However, no signifi cant effect of mood management was observed when both the target and control groups received equal therapist time (Hall et al. 1996). Mood manage ment did not attenuate postcessation increases in depression among smokers with a past history of depression.
Other types of psychotherapy might be more effective than mood manage ment in treating people with comorbid nicotine dependence and depression. Brown and colleagues (2001) found that heavy smokers with a history of major depressive disorder had better outcomes when cognitive behavioral therapy (CBT) for depression was incorporated into a standard smoking cessation treatment. Although CBT for depression did not decrease depressive symptoms prior to or after smoking cessation, it did prevent the expected rise in such symptoms following smok ing cessation. In a recent review of combination treatment for nicotine dependence, Ingersoll and Cohen (2005) reported that treatments com bining a behavioral component with a first-line pharmacotherapeutic agent enhanced smoking cessation rates more than either alone. They concluded that some forms of psychosocial treatment, "such as those based on principles of effective brief therapies, and using tech niques of CBT, can enhance the gains achieved with first-line pharmacothera pies for smoking cessation in general populations of smokers." Depressed women appear to be par ticularly responsive to certain types and modalities of psychotherapy adminis tration. For instance, Ginsberg and col leagues (1997) have reported that group CBT was an effective and impor tant part of a multicomponent (CBT plus nicotine gum) smoking cessation program for women with and without a history of depression. In that study, standard smoking cessation group CBT included learning strategies for smoking cessation, goal setting for nicotine fading, increased social sup port, problem-solving skills training, and, finally, weaning off gum after quitting nicotine. This type of CBT, which emphasizes group cohesion and social support, helped to maintain adherence, thereby promoting effective treatment and smoking cessation regardless of whether there was a his tory of depression. One caveat to this study is that the authors did not evalu ate the impact of the treatment on depressive symptoms.
Alcohol dependence complicates the pathophysiology, course, and treatment outcome of depressed smokers. Patten and colleagues (2002) found that smokers with a history of alcohol dependence, who also reported high levels of depressive symptoms, were more likely to be abstinent from smok ing at the end of treatment and at fol low-up than those with low depression scores. Thus, Zelman and colleagues (1992) have proposed that smokers who are vulnerable to negative affectand who use drugs to regulate moodmight benefit more from a mood man agement-specific therapy to address their depression in addition to smoking cessation treatment.
In summary, incorporating a behav ioral intervention with pharmacother apy for smoking cessation increases the success rate, perhaps because of an improved adherence to treatment. CBT that emphasizes group cohesion and social support appears to be benefi cial in maintaining treatment adher ence among depressed smokers within smoking cessation treatment and helps to prevent the expected rise in depres sive symptoms upon quitting. The added benefit of teaching mood man agement skills has, however, not been established in the treatment of depressed smokers with or without alcohol dependence.

Gender-and Age-Specific Issues Associated With Treatment Outcome
Rates of smoking are much higher among people who have alcohol prob lems and a history of depressive ill nesses than among people without those disorders (Currie et al. 2001). Depression also is associated with ear lier relapse in treated teens with alcohol use disorder (Cornelius et al. 2004) as well as in adult alcoholics (Greenfield et al. 1998). Among smokers, females tend to have a worse problem abstain ing from nicotine than their male counterparts (Perkins et al. 1999). There are, at least, two possible expla nations for this gender difference. First, among smokers, women are more con cerned than men about weight gain following smoking cessation. Second, because women are more prone to affective disorder, they tend to have greater negative affect associated with smoking cessation. Nevertheless, research in this area is still developing, and little is known about the gender-and agespecific issues associated with treatment outcome among depressed smokers who also are alcohol dependent.

Conclusions
People with concurrent mental disor ders, such as major depression and alco hol and nicotine dependence, are increasingly prevalent in clinical prac tice and generally have poor response to treatments, which can be costly. Nevertheless, there is growing evidence that contemporaneous treatment for depressive disorder and smoking cessa tion is preferable to treatment of either condition alone, even in the presence of alcohol dependence. In such cases, combining different pharmacological agents in conjunction with CBT or other psychotherapies appears to be the preferred mode of treatment. New medications such as topiramate that could treat both alcohol and nicotine dependence might simplify the use of combination therapies if there is a con comitant depressive illness. The devel opment of more specific pharmacologi cal strategies targeting the populations most likely to respond-or working at different phases of the disorder(s)-is in its infancy. Among the various psy chotherapies, CBT that emphasizes group cohesion and social support appears to be particularly useful for treating depressed smokers with or with out alcohol dependence. The necessity of teaching mood management skills among people with nicotine and alco hol dependence who are also depressed has not been established. New knowl edge is needed to develop treatments that might benefit special populations, including women and teenagers. ■